Bone defects, both large and small, from non-unions or trauma patients, pose a significant challenge and often require surgical intervention. See, e.g., Drosse I. (2008) “Tissue engineering for bone defect healing: an update on a multi-component approach.” Injury 39:S9-20). In the U.S. alone, 1.3 million people undergo bone graft surgeries each year with skeletal defects either from accidents or disease (Langer R and Vacanti J P (1993) “Tissue Engineering”. Science 260:920-926). However, current treatments mostly rely on autografts or allografts but have associated risks, with autografts needing an additional surgical site and limited in supply, while allografts have potential risks of disease transmission and long term complications. See, e.g., Marquis M E et al. (2009) “Bone cells biomaterials interactions.” Front Biosci 14:1023-1067; Khan Y et al. (2008) “Tissue engineering of bone: material and matrix considerations.” J Bone Joint Surg Am 90:36-42.
Tissue engineering represents a promising solution towards repair and replacement of these diseased and damaged bone tissues with engineered grafts. Towards this goal, a wide range of natural and synthetic biodegradable polymers has been evaluated, including hyaluronic acid, chitosan, poly(L-lactide-co-glycolide) (PLGA), polycaprolactone (PCL), polymethylmethacrylate (PMMA) as well as several ceramic materials such as calcium phosphate, calcium sulfate and bioactive glass. See, e.g., Dawson J I, et al. (2008) “Development of specific collagen scaffolds to support the osteogenic and chondrogenic differentiation of human bone marrow stromal cells.” Biomaterials 29:3105-3116; Pek Y S et al. (2008) “Porous collagen apatite nanocomposite foams as bone regeneration scaffolds.” Biomaterials 29:4300-4305; Oliveira J M et al. (2006) “Novel hydroxyapatite/chitosan bilayered scaffold for osteochondral tissue engineering applications: Scaffold design and its performance when seeded with goat bone marrow stromal cells.” Biomaterials 27:6123-6137; Le Nihouannen D. et al. (2006) “Micro-architecture of calcium phosphate granules and fibrin glue composites for bone tissue engineering.” Biomaterials 27:2716-2722; Sikavitsas V I et al. (2002) “Formation of three-dimensional cell/polymer constructs for bone tissue engineering in a spinner flask and a rotating wall vessel bioreactor.” J Biomed Mater Res 62:136-148; Ochi K, et al., (2003) “Use of isolated mature osteoblasts in abundance acts as desired-shaped bone regeneration in combination with a modified poly-DL-lactic-co-glycolic acid (PLGA)-collagen sponge.” J Cell Physiol 194:45-53; Zhang K et al. (2002) “Porous polymer/bioactive glass composites for soft to hard tissue interfaces.” J Biomed Mater Res 61:551-563; Hutmacher D W et al. (2001) “Mechanical properties and cell cultural response of polycaprolactone scaffolds designed and fabricated via fused deposition modeling.” J Biomed Mater Res 55:203-216. Each of these materials presents limitations in achieving the requirements for bone repair scaffolds mentioned earlier. For example, PCL is biocompatible, resorbable and slowly degradable; however its use is limited due to its failure to promote osteogenesis without premineralization. See, e.g., Del Gaudio C. et al. (2006) “Assessment of electrospun PCL scaffold for tissue engineering.” Int J Artif Organs 29:537-537; Izquierdo R. et al. (2008) “Biodegradable PCL scaffolds with an interconnected spherical pore network for tissue engineering.” J Biomed Mater Res A 8:25-35; Liao J. et al. (2010) “Modulation of osteogenic properties of biodegradable polymer/extracellular matrix scaffolds generated with a flow perfusion bioreactor.” Acta Biomater 6:2386-2393. Similarly, collagen and/or collagen-based scaffold have a lower compressive modulus of 0.034 MPa, failing to reach 10-50 MPa of native cancellous bone. See, e.g., Dawson J I. et al. (2008) Biomaterials 29:3105-3116; Xiao Y. et al. (2003) “Tissue engineering for bone regeneration using differentiated alveolar bone cells in collagen scaffolds.” Tissue Eng 9:1167-1177; Yang X B B. et al. (2004) “Biomimetic collagen scaffolds for human bone cell growth and differentiation.” Tissue Eng 10:1148-1159; Hodgskinson R and Currey J D (1992) “Young modulus. Density and material properties in cancellous bone over a large density range.” J Mater Sci Mater M 3:377-381; Yaszemski M J. et al. (1996) “Evolution of bone transplantation: Molecular, cellular and tissue strategies to engineer human bone.” Biomaterials 17:175-185.
To improve on the mechanical properties and osteoinductive potential of bone scaffold materials, the use of composites has been explored. The use of ceramic materials such as tri-calcium phosphates, hydroxyapatite (HAP), or bioactive glass as inclusions in polymer matrices is often used to enhance mechanics. See, e.g., Zhang K. et al. (2002) J Biomed Mater Res 61:551-563; Khan Y M. et al. (2004) “Novel polymer-synthesized ceramic composite-based system for bone repair: an in vitro evaluation.” J Biomed Mater Res A 69:728-737; Thein-Han W W. et al. (2009) “Superior in vitro biological response and mechanical properties of an implantable nanostructured biomaterial: nano hydroxyapatite-silicone rubber composite. “Acta Biomater 5:2668-2679; Wei G B and Ma P X (2004) “Structure and properties of nano-hydroxyapatite/polymer composite scaffolds for bone tissue engineering.” Biomaterials 25:4749-4757; Zhang Y. et al. (2010) “The osteogenic properties of CaP/silk composite scaffolds.” Biomaterials 31:2848-2856. The addition of PLGA microspheres with calcium phosphate followed by sintering yielded highly interconnected structures with mechanics similar to trabecular bone in the dry state (Khan Y M. et al. (2004) J Biomed Mater Res A 69:728-737). In another report, silicone rubber with dispersion of nano-hydroxyapatite (nHAP) had improved surface properties for pre-osteoblasts when compared to pure silicone rubber, resulting in enhanced cell attachment, viability and proliferation (Thein-Han W W. et al. (2009) Acta Biomater 5:2668-2679).
However, many challenges remain to satisfy an optimally functional bone regeneration scaffold system (Salgado A J. et al. (2004) “Bone tissue engineering: State of the art and future trends.” Macromol Biosci 4:743-765). In particular, a need for polymer materials to meet the high compressive properties of load-bearing bone is an important prerequisite to function in vivo. See, e.g., Gil E S. et al. (2011) “Mechanical improvements to reinforced porous silk scaffolds.” J Biomed Mater Res Part A 99:16-28; Rockwood D N. et al. (2011) “Ingrowth of human mesenchymal stem cells into porous silk particle reinforced silk composite scaffolds: An in vitro study.” Acta Biomaterialia 7:144-151; Zhou Y F, et al. (2007) Combined marrow stromal cell-sheet techniques and high strength biodegradable composite scaffolds for engineered functional bone grafts. Biomaterials 28:814-824; Leong K F. et al. (2003) “Solid freeform fabrication of three-dimensional scaffolds for engineering replacement tissues and organs.” Biomaterials 24:2363-2378; Vitale-Brovarone C. et al. (2009) “High strength bioactive glass-ceramic scaffolds for bone regeneration.” J Mater Sci Mater M 20:643-653. Thus, there is still a need for development of engineered grafts with a compressive strength comparable to a load-bearing bone, which can be used for bone repair.